Convenient direct reductive amination of carbonyl compounds in a completely aqueous media

Article abstract of DOI:10.2174/157017810791514715

We report hereby a particularly efficient synthesis of secondary, and tertiary amines respectively, through a direct reductive amination process carried for the first time in a completely aqueous media.

Full text of DOI:10.2174/157017810791514715

3
88
Letters in Organic Chemistry, 2010, 7, 388-391
Convenient Direct Reductive Amination of Carbonyl Compounds in a
Completely Aqueous Media
,a
a
b
b
b
Cristian Simion* , Alina M. Simion , Takashi Arimura , Akira Miyazawa and Masashi Tashiro
a
"Politehnica" University of Bucharest, Faculty of Applied Chemistry and Material Science, Organic Chemistry
Department, Spl. Independentei nr. 313, Bucharest, 060042, Romania
b
National Institute of Advanced Science and Technology, AIST Central 5, Tsukuba, Ibaraki, 305-8565, Japan
Received March 02, 2010: Revised March 11, 2010: Accepted March 15, 2010
Abstract: We report hereby a particularly efficient synthesis of secondary, and tertiary amines respectively, through a
direct reductive amination process carried for the first time in a completely aqueous media.
Keywords: Direct reductive amination, Pd/C, Al, aqueous media.
INTRODUCTION
with ammonia and molecular hydrogen in an aqueous THF
solution using water-soluble catalysts such as [Rh(COD)Cl]
2
,
Synthesis of secondary or tertiary amine through
successive condensation-reduction steps is known as direct
reductive amination (DRA) and represents a highly useful
tool in the hands of organic chemists in order to generate a
large variety of important aza-precursors, intermediates and
biologically active compounds which are highly abundant in
pharmaceutical [1] or agrochemical industries [2].
Consequently, the array of methods for the generation of
amine moieties has seen a constant expansion, with a certain
enhancement for the usefulness of different complex
reduction catalysts [3]. It is noteworthy that most of the
existing methods belong to two main classes, which are
catalytic hydrogenation [4] and hydride reagent reduction
but at high pressure and temperature [7]. Milder conditions
were used by Nait Ajjou [8]; in this case, the catalyst was a
water-soluble, complex and stable Pd species. Nevertheless,
molecular hydrogen must also be provided and the reaction
time is excessively long (24 hours) [8].
RESULTS AND DISCUSSION
It is accepted that the DRA process occurs through a 2-
step pathway: a first condensation that yields an imine which
suffers subsequent hydrogenation/reduction, according to the
reaction conditions [9]. We have already demonstrated that
imines can be easily obtained in a simple procedure by
working only in an aqueous media [10]. On the other hand,
we also conducted several reductive processes in which
water plays the role of a hydrogen donor, under the action of
a metal such as Al or Zn [11]. Moreover, there are literature
reports of homogenous DRA processes using a noble metal
catalyst complex and a polar solvent such as methanol,
although in that case the amine moiety is hydrogenated with
[
5]. However, most of these methods present several
disadvantages when considering their harmful potential, both
for humans and the environment: for instance, reducing
agents such as sodium cyanoborohydride (NaBH
or pyridine-borane (Py-BH ) [5d,e], which are highly toxic
and thermally unstable, sodium triacetoxyborohydride
NaBH(OAc) ) [5f], which is flammable, or poisonous tin-
3
CN) [5a-c]
3
(
3
or titanium-based catalysts [5g-l] are all a threat to human
health and to the environment. On the other hand, even if
catalytic hydrogenation methods seem more attractive from
the point of view of costs, they need high pressure of
flammable hydrogen gas and frequently a heterogeneous
reaction media. Other disadvantages common to both
families are the use of high excess of amine and expensive
molecular H introduced from an external source, rather than
2
reduced with in situ generated hydrogen [12]. We decided to
combine these aspects and attempt the synthesis of
secondary and tertiary amines in a simple and mild DRA
process, in a completely aqueous media and using a simple
catalyst, such as a noble metal deposed on charcoal and Al
powder (Scheme 1), without any external source of
(
and most of the time also toxic) organic solvents. With the
rise of the concept of Green chemistry, several research
teams turned their eyes toward water as a possible
environmentally-friendly solvent for such a process. Thus,
Kikugawa and co-workers introduced a DRA process carried
out in a mixture of water and acetic acid (10:1) and in the
presence of ꢀ-picoline-borane as reducing agent [6], while
Beller and co-workers reported the first DRA of aldehydes
R1
R
NH2
CH NH
R
R1
R2
R2
R1
Met/C + Al
H O, 120°C, 30 min
C
O
2
R
CH
N
R
NH
R
*
Address correspondence to this author at the “Politehnica” University of
Bucharest, spl. Independentei nr. 313, 060042, Bucharest, Romania; Tel:
0-21-402-3948; E-mail: c_simion@chim.upb.ro
R2
R
4
Scheme 1.
1
570-1786/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

Convenient Direct Reductive Amination of Carbonyl Compounds
Letters in Organic Chemistry, 2010, Vol. 7, No. 5
389
R1
Met/C + Al
CH
NH
R1
CHO
R2
NH2
R1
CH
N
R2
R1
+
+
R2
+
H O
2
1
2
3
4
R1
CH
N
R
2
5
R = CH (CH )
R = CH (CH )
2 3
1
3
2 5
2
3
Scheme 2.
Table 1. Effect of Different Met/C Catalysts
a
Reaction products (yield, %)
5
Entry
Cat. + Al
3
4
2 (recovered)
1
5% Pd/C
5% Pt/C
5% Rh/C
5% Ru/C
traces
traces
traces
22
41
60
52
26
30
14
20
30
29
26
28
15
2
3
4
a
Established by GC-MS.
R
NH2
hydrogen, water playing the role of hydrogen provider. Our
hypothesis is that in a first step a condensation process takes
place, with subsequent formation of an imine [10], the latter
being reduced in situ in the next stage.
O
NH
R
Met/C + Al
H O, 120°C, 30 min
2
6
7
In the first step we tested the effectiveness of some of our
catalytic systems formed of a noble metal (such as Pt, Pd, Rh
or Ru) deposed on charcoal and Al powder - the part of Al is
to generate hydrogen from water, while the noble metal
catalyses the subsequent reduction process of the in situ
formed imine. Thus, we submitted an equimolecular mixture
of aldehyde and amine, in water, to the catalytic action of the
system Met/C-Al (Scheme 2). In a typical reaction protocol,
the equimolecular mixture of aldehyde and amine (1.0 mmol
each) is introduced in 2 mL water; 100 mg of Al powder and
Scheme 3.
Table 2. DRA of Cyclohexanone with Various Amines
*
Entry
Amine
Cat + Al
Yield (%)
1
2
n-Butylamine
2-Ethyl-n-butylamine
n-Hexylamine
n-Octylamine
Pt/C
Pt/C
Pt/C
Pt/C
Pt/C
Pd/C
Rh/C
Ru/C
Pt/C
Pt/C
Pt/C
Pt/C
89
76
98
68
99
61
60
18
96
93
89
71
3
4
1
00 mg of Met/C are added in one portion. The reaction
5
Cyclo-Pentylamine
Cyclo-Pentylamine
Cyclo-Pentylamine
Cyclo-Pentylamine
Tetrahydropyrrole
Piperidine
mixture is stirred in a sealed tube, heated at 120°C for 30
minutes. After subsequent extraction with diethyl ether and
drying on MgSO , the crude reaction mixture is submitted to
4
GC-MS analyses. For our first attempts we chose a linear
aliphatic aldehyde and an aliphatic amine, which finally
proved to be a poor choice of starting materials:
6
7
8
9
Indeed, the choice of a linear aliphatic aldehyde was not
an inspired one, since the final reaction mixture was rather a
complex one. But, although the yields in the main reaction
product were low (26-60%), this series of experiments
showed us that: 1) Pt/C seems to be the best catalyst in the
series; 2) the recording of traces or higher quantities of
Schiff bases confirms the general pathway of the process,
even if working in aqueous media, which is in agreement
with our starting hypothesis and 3) main secondary product
is, in this case, the ꢀ,ꢁ-unsaturated imine, formed by a
crotonization process, examples of such behavior being
already known [13]. Nevertheless, the most important
information is the one regarding the nature of the catalyst.
For the next series of experiments we kept as catalytic
system Pt/C-Al and used a less reactive carbonyl compound:
cyclohexanone 6 (Scheme 3). For this ketone we attempted
also the synthesis of tertiary amines; yields in secondary and
tertiary amines were high, regardless of the nature of the
starting amines (Table 2):
10
1
1
Pyrrole
12
Established by GC-MS.
Pyridine
*
It is interesting to note that in entries 6-7 the use of Pd or
Rh affords the corresponding secondary amine with fair
yields (60%, respectively 61%), although lower than those
for Pt/C, while only traces of other secondary products, such
as di-cyclopentylamine and di-cyclo-hexylamine, are
recorded. The process was attempted also in the presence of
Ru, although we were aware of the fact the yields will
probably be very low (see Table 1, entry 4), but in this case
the ratio and nature of secondary products were more
important, giving us a glance on the possible intermediates
and reaction pathway. Indeed, although the corresponding
imine is present only as traces in the final reaction mixture,
the formation of high amounts of di-cyclopentylamine and

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90 Letters in Organic Chemistry, 2010, Vol. 7, No. 5
Simion et al.
NH or
NH
N
N
+
+
8
0
9
O
Pt/C + Al
H O, 120°C, 30 min
traces
2
6
N
N
NH or
N
1
11
traces
Scheme 4.
di-cyclohexylamine can be explained only through Schiff
base formation, isomerization and subsequent hydrolysis
having as final transamination product the cyclohexylamine,
which is the starting material for the dicyclohexylamine
generation. When working with tetrahydropyrrole or
piperidine (Scheme 4), longer reaction time didn’t improve
the yield. Since one of our previous application for the
catalytic system Met/C-Al was the reduction of aromatic
rings [11e], we tried as starting nitrogen compound the
cheaper pyrrole and pyridine instead of tetrahydropyrrole or
piperidine, and remarkably, the corresponding N-
cyclohexyltetrahydropyrrole and N-cyclohexyl-piperidine
were formed (Scheme 4). In these 4 cases (entries 9-12),
traces of the corresponding enamine (which seem to be, in
this case, the reaction intermediate) were recorded.
(transformation of the starting materials was almost
quantitative), but Pd and Rh gave also high yields in
secondary amine formation (96%, respectively 87%). As a
detail, traces of the reduction products of benzaldehyde
(toluene and benzyl alcohol) were detected. Our next step
was to attempt the synthesis of tertiary amines, using as
starting material a secondary amine, such as piperidine
(entries 5-7, Table 3):
Entry 5-7 required a longer reaction time (~ 2 hours) than
the first attempts, for which 30 minutes were sufficient to
complete the reaction. In the same manner as previously
described, pyridine behaved similarly with piperidine, both
yielding the corresponding N-benzylpiperidine (entry 7). In
entry 4, when Ru/C is used, the main reaction product
(
pointing to a 41% yield) was the corresponding imine, N-
Same reaction protocol was applied to aromatic
aldehydes (a logical choice, since these carbonyl compounds
cannot suffer crotonization), (Scheme 5): when mixing
equimolecular amounts of benzaldehyde and n-butylamine,
main reaction product was n-butyl-benzylamine (entries 1-4,
Table 3). Here again Pt/C proved to be best suited catalyst
benzyliden-butylamine, which confirmed the general 2-step
pathway of the DRA (step 1: condensation and imine
formation; step 2: reduction of the intermediate imine).
In conclusion, we described the first completely
environmentally-friendly DRA process, with a simple
n-C H -NH
2
4
9
CH OH
+
CH
2
NH
C H
4 9
2
13
14
Met/C + Al
CHO
H O, 120°C, 30 min
2
1
2
CH OH
+
CH2
15
N
2
NH or
N
13
Scheme 5.
Table 3. DRA of Benzaldehyde with Various Primary and Secondary Amines
Reaction Products (Yield %)*
Recovery of Starting Amine Intermediate Imine / Enamine
Entry
Aldehyde
Amine
Cat + Al
1
3
14 / 15
1
2
3
4
5
6
7
C
6
C
6
C
6
C
6
C
6
C
6
C
6
H
H
H
H
H
H
H
5
5
5
5
5
5
5
-CHO
-CHO
-CHO
-CHO
-CHO
-CHO
-CHO
n-Butylamine
n-Butylamine
n-Butylamine
n-Butylamine
Piperidine
Pt/C
Pd/C
Rh/C
Ru/C
Pt/C
-
~100
96
-
-
-
2
7
2
87
6
-
13
7
32
8
41
-
77
16
30
10
Piperidine
Pd/C
Pt/C
18
20
40
11
-
Pyridine
70
*
Established by GC-MS.

Convenient Direct Reductive Amination of Carbonyl Compounds
Letters in Organic Chemistry, 2010, Vol. 7, No. 5
391
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